Discrepant alterations in main candidate genes among multiple primary melanomas

BackgroundAlterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM).MethodsOne hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with four) were included into the study. Paired synchronous/asynchronous MPM tissues (N = 229) were analyzed for BRAF mutations and cKIT/CyclynD1 gene amplifications.ResultsBRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1 amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p < 0.001) and CyclinD1 (p = 0.002) amplification rates was observed between first and subsequent primary melanomas. Among the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant pattern of BRAF mutations as compared to incident primary tumors.ConclusionsThe low consistency in somatic mutation patterns among MPM lesions from same patients provides further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary melanomas.

[1]  R. Scolyer,et al.  Cutaneous melanoma in the era of molecular profiling , 2009, The Lancet.

[2]  S. Rosso,et al.  Clinicopathologic Features of Incident and Subsequent Tumors in Patients with Multiple Primary Cutaneous Melanomas , 2012, Annals of Surgical Oncology.

[3]  Martin F. Mihm,et al.  Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”: Napoli, December 3rd–6th 2014 , 2013, Journal of Translational Medicine.

[4]  P. Lopez-Bergami.  The role of mitogen‐ and stress‐activated protein kinase pathways in melanoma , 2011, Pigment cell & melanoma research.

[5]  L. Chin,et al.  The INK4a/ARF locus and melanoma , 2003, Oncogene.

[6]  T. Saida,et al.  Molecular Diagnostics , 2013, BioMed research international.

[7]  F. Marincola,et al.  Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012” , 2013, Journal of Translational Medicine.

[8]  D. Whiteman,et al.  Anatomic site, sun exposure, and risk of cutaneous melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  K. Aldape,et al.  Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. , 2013, The Journal of molecular diagnostics : JMD.

[10]  A. D. Van den Abbeele,et al.  Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  J. Choi,et al.  Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta‐analysis , 2011, The British journal of dermatology.

[12]  A. Stromberg,et al.  Second Primary Melanomas: Incidence and Outcome , 2010, The American surgeon.

[13]  A. Hauschild,et al.  Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  M. Mihatsch,et al.  Anatomic site-specific patterns of gene copy number gains in skin, mucosal, and uveal melanomas detected by fluorescence in situ hybridization , 2006, Virchows Archiv.

[15]  Jeffrey E Gershenwald,et al.  Final version of 2009 AJCC melanoma staging and classification. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  R. Sullivan,et al.  MAP kinase signaling and inhibition in melanoma , 2013, Oncogene.

[17]  K. Flaherty,et al.  Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma , 2011, Clinical Cancer Research.

[18]  Hong Wu,et al.  Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas , 2008, Molecular Cancer Therapeutics.

[19]  N. Hayward,et al.  Molecular Pathways: Mitogen-Activated Protein Kinase Pathway Mutations and Drug Resistance , 2013, Clinical Cancer Research.

[20]  G. Botti,et al.  Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma , 2013, Journal of Translational Medicine.

[21]  B. Schilling,et al.  Future perspectives in melanoma research: meeting report from the “Melanoma Bridge”, Napoli, December 5th-8th 2013 , 2014, Journal of Translational Medicine.

[22]  P. Ascierto,et al.  Main roads to melanoma , 2009, Journal of Translational Medicine.

[23]  D. Schadendorf,et al.  Somatic alterations in the melanoma genome: A high‐resolution array‐based comparative genomic hybridization study , 2010, Genes, chromosomes & cancer.

[24]  F. Izzo,et al.  BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy , 2012, Cell Death and Disease.

[25]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[26]  G. Botti,et al.  BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  F. Hodi,et al.  Molecular genetics of familial cutaneous melanoma. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  F. Sommerer,et al.  Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma , 2003, Gut.

[29]  T. Hamilton,et al.  Multiple primary melanomas. , 1998, Journal of the American Academy of Dermatology.

[30]  P. Carli,et al.  Multiple synchronous cutaneous melanomas: implications for prevention , 2002, International journal of dermatology.

[31]  R. Ádány,et al.  Characterization of candidate gene copy number alterations in the 11q13 region along with BRAF and NRAS mutations in human melanoma , 2009, Modern Pathology.

[32]  L. Heinzerling,et al.  Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations , 2013, British Journal of Cancer.

[33]  J. Fridlyand,et al.  Distinct sets of genetic alterations in melanoma. , 2005, The New England journal of medicine.

[34]  J. Stein,et al.  Single versus multiple primary melanomas , 2012, Cancer.

[35]  P. Boyle,et al.  Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. , 2005, European journal of cancer.

[36]  A. Halpern,et al.  Clinicopathological features of and risk factors for multiple primary melanomas. , 2005, JAMA.

[37]  A. Chompret,et al.  Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families. , 2004, Journal of the National Cancer Institute.

[38]  M. Oliviero,et al.  Multiple primary melanomas: do they look the same? , 2013, The British journal of dermatology.

[39]  G. Pupo,et al.  Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma , 2013, Molecular Cancer Therapeutics.

[40]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[41]  P. Laurent-Puig,et al.  Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group , 2013, BMC Cancer.

[42]  K. Flaherty,et al.  The MAPK pathway in melanoma , 2008, Current opinion in oncology.

[43]  D. Pinkel,et al.  Cyclin D1 is a candidate oncogene in cutaneous melanoma. , 2002, Cancer research.

[44]  Susan Muller,et al.  KIT Gene Mutations and Copy Number in Melanoma Subtypes , 2008, Clinical Cancer Research.

[45]  D. Pinkel,et al.  Somatic activation of KIT in distinct subtypes of melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  Dennis C. Friedrich,et al.  MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. , 2014, Cancer discovery.

[47]  V. de Giorgi,et al.  Multiple primary melanoma: the impact of atypical naevi and follow up , 2010, The British journal of dermatology.